Opioid drug-induced ventilatory depression is a common clinical problem and a significant cause of perioperative morbidity. The overall hypothesis of this proposal is that such respiratory depression may be overcome by pharmacological intervention. Specifically, we will test the hypothesis that inhibition of TASK-1 and TASK-3 tandem pore potassium channel function in the carotid body stimulates breathing and prevents morphine-induced ventilatory depression. The carotid body is essential for regulation of breathing by hypoxia and hypercarbia, and the TASK-1 and TASK-3 heterodimer potassium channel provides the predominant hypoxia-sensitive potassium conductance in carotid body chemosensing cells. The drug doxapram stimulates breathing through carotid body activation and is a potent TASK-1 and TASK-3 potassium channel antagonist. We have identified two additional TASK-1 and TASK-3 antagonist compounds that stimulate breathing with an efficacy, potency, and duration that markedly exceed that of doxapram. Our preliminary data also suggest these agents may prevent morphine-induced depression of breathing at supralethal doses. In Aims 1 and 2, we propose studies to determine if the carotid body and, more specifically, if TASK-1 and TASK-3 potassium channels within the carotid are the sites of action through which the TASK antagonist compounds stimulate breathing. We will quantify rat breathing before and after administration of the TASK antagonist compounds using plethysmography and blood gas analysis. We will study rats with and without surgically denervated carotid bodies, and we will study rats expressing antagonist-resistant mutant TASK-3 subunits in their carotid bodies. These antagonist-resistant TASK-3 mutants will be identified in our proposed studies. In Aim 3, we will use dynamic end-tidal forcing to characterize the effect of each TASK antagonist on breathing regulation by hypoxia and hypercarbia. Finally, in Aim 4, we will confirm the efficacy of TASK antagonists in reversing and preventing morphine-induced depression of breathing, and we will determine the effect of TASK antagonists on morphine analgesia. If our hypothesis is correct, these studies will validate TASK-1 and TASK-3 potassium channels as a therapeutic target for treatment of breathing disorders and will provide a novel pharmacologic strategy to improve patient safety during opioid administration.